Daniel Hungerford

Early impact of rotavirus vaccination in a large paediatric hospital in the UK

The impact of routine rotavirus vaccination on community-acquired (CA) and healthcare-associated (HA) rotavirus gastroenteritis (RVGE) at a large paediatric hospital, UK, was investigated over a 13-year period. A total of 1644 hospitalized children aged 0-15 years tested positive for rotavirus between July 2002 and June 2015. Interrupted time-series analysis demonstrated that, post vaccine introduction (July 2013 to June 2015), CA- and HA-RVGE hospitalizations were 83% [95% confidence interval (CI): 72-90%) and 83% (95% CI: 66-92%] lower than expected, respectively. Rotavirus vaccination has rapidly reduced the hospital rotavirus disease burden among both CA- and HA-RVGE cases.

Effect of socioeconomic deprivation on uptake of measles, mumps and rubella vaccination in Liverpool, UK over 16 years: a longitudinal ecological study

Suboptimal uptake of the measles, mumps and rubella (MMR) vaccine by certain socioeconomic groups may have contributed to recent large measles outbreaks in the UK. We investigated whether socioeconomic deprivation was associated with MMR vaccine uptake over 16 years. Using immunization data for 72,351 children born between 1995 and 2012 in Liverpool, UK, we examined trends in vaccination uptake. Generalized linear models were constructed to examine the relative effect of socioeconomic deprivation and year of birth on MMR uptake. Uptake of MMR1 by age 24 months ranged between 82·5% in 2003 [95% confidence interval (CI) 81·2-83·7] and 93·4% in 2012 (95% CI 92·7-94·2). Uptake of MMR2 by age 60 months ranged between 65·3% (95% CI 64·4-67·4) in 2006 and 90·3% (95% CI 89·4-91·2) in 2012. In analysis adjusted for year of birth and sex, children in the most deprived communities were at significantly greater risk of not receiving MMR1 [risk ratio (RR) 1·70, 95% CI 1·45-1·99] and MMR2 (RR 1·36, 95% CI 1·22-1·52). Higher unemployment and lower household income were significantly associated with low uptake. Contrary to concerns about lower MMR uptake in affluent families, over 16 years, children from the most socioeconomically deprived communities have consistently had the lowest MMR uptake. Targeted catch-up campaigns and strategies to improve routine immunization uptake in deprived areas are needed to minimize the risk of future measles outbreaks.

Population effectiveness of the pentavalent and monovalent rotavirus vaccines: a systematic review and meta-analysis of observational studies

BackgroundRotavirus was the leading cause of acute gastroenteritis (AGE) in infants and young children prior to the introduction of routine vaccination. Since 2006 there have been two licensed vaccines available; with successful clinical trials leading the World Health Organization to recommend rotavirus vaccination for all children worldwide. In order to inform immunisation policy we have conducted a systematic review and meta-analysis of observation studies to assess population effectiveness against acute gastroenteritis.MethodsWe systematically searched PubMed, Medline, Web of Science, Cinhal and Academic Search Premier and grey literature sources for studies published between January 2006 and April 2014. Studies were eligible for inclusion if they were observational measuring population effectiveness of rotavirus vaccination against health care attendances for rotavirus gastroenteritis or AGE. To evaluate study quality we use used the Newcastle-Ottawa Scale for non-randomised studies, categorising studies by risk of bias. Publication bias was assessed using funnel plots. If two or more studies reported a measure of vaccine effectiveness (VE), we conducted a random effects meta-analysis. We stratified analyses by World Bank country income level and used study quality in sensitivity analyses.ResultsWe identified 30 studies, 19 were from high-income countries and 11 from middle-income countries. Vaccine effectiveness against hospitalization for laboratory confirmed rotavirus gastroenteritis was highest in high-income countries (89% VE; 95% CI 84-92%) compared to middle-income countries (74% VE; 95% CI 67-80%). Vaccine effectiveness was higher for those receiving the complete vaccine schedule (81% VE; 95% CI 75-86%) compared to partial schedule (62% VE; 95% CI 55-69%). Two studies from high-income countries measured VE against community consultations for AGE with a pooled estimate of 40% (95% CI 13-58%; 2 studies).ConclusionsWe found strong evidence to further support the continued use of rotavirus vaccines. Vaccine effectiveness was similar to that reported in clinical trials for both high and middle-income countries. There is limited data from Low income settings at present. There was lower effectiveness against milder disease. Further studies, should continue to report effectiveness against AGE and less-severe rotavirus disease because as evidenced by pre-vaccine introduction studies this is likely to contribute the greatest burden on healthcare resources, particularly in high-income countries.

Identifying areas and risk groups with localised Mycobacterium tuberculosis transmission in northern England from 2010 to 2012: spatiotemporal analysis incorporating highly discriminatory genotyping data

Background Information on geographical variation in localised transmission of TB can inform targeting of disease control activities. The aim of this study was to estimate the proportion of TB attributable to localised transmission for the period 2010–2012 in northern England and to identify case characteristics associated with spatiotemporal-genotypical clusters. Methods We combined genotyping data with spatiotemporal scan statistics to define an indicator of localised TB transmission and identified factors associated with localised TB transmission thus defined in a multivariable logistics regression model. Results The estimated proportion of TB cases in northern England attributable to localised transmission was 10% (95% CI 9% to 12%). Clustered cases (cases which were spatiotemporally clustered with others of identical genotype) were on average younger than non-clustered cases (mean age 34 years vs 43 years; p value <0.05). Being UK born (adjusted OR (aOR) 3.6, 95% CI 2.9 to 6.0), presenting with pulmonary disease (aOR 2.2, 95% CI 1.3 to 3.6) and history of homelessness (aOR 2.8, 95% CI 1.2 to 6.8) or incarceration (aOR 2.6, 95% CI 1.2 to 5.9) were independently associated with being part of a spatiotemporal-genotypical cluster in a multivariable model. Belonging to an ethnic group other than white or mixed/other was also significantly associated with localised transmission. We identified localised transmission in 103/1958 middle super output areas mostly in urban areas. Conclusions Incorporating highly discriminatory genotyping data into spatiotemporal analysis of TB incidence is feasible as part of routine surveillance and can provide valuable information on groups at greater risk and areas with localised transmission of TB, which could be used to inform control measures, such as intensified contact tracing.

Uptake of a new meningitis vaccination programme amongst first-year undergraduate students in the United Kingdom: A cross-sectional study

Background In 2015 meningococcal group W was declared endemic in the UK, with the meningococcal ACWY vaccination (MenACWY) subsequently introduced amongst adolescents and first-year university students. This study aimed to determine MenACWY uptake amongst students and to evaluate how this was influenced by demographics and via the Health Belief Model (HBM). Methods This was a cross-sectional study conducted at a British university amongst first-year undergraduate students aged 18–25 years. Data collection was via an electronic questionnaire encompassing demographics, the HBM and vaccination status. Univariable analysis of the associations between demographics, health beliefs and vaccination was performed, followed by multiple logistic regression. Results 401 participants were included in analysis. Vaccine uptake was 68.1%. Variables independently associated with vaccination upon multiple regression were age, gap-year, perceived effectiveness of the vaccine and knowledge about risk of meningitis. Compared to 18 year-olds, the odds of vaccination were reduced for 19 year-olds (aOR = 0.087, 95% CI = 0.010–0.729), 20 year-olds (aOR = 0.019, 95% CI = 0.002–0.161) and 21–25 year-olds (aOR = 0.003, 95% CI = <0.001–0.027). In contrast, taking a gap year (aOR = 2.939, 95% CI = 1.329–6.501), higher perceived vaccine effectiveness (aOR = 3.555, 95% CI = 1.787–7.073) and knowledge about meningitis risk (aOR = 2.481, 95% CI = 1.165–5.287) were independently associated with increased uptake. Conclusions MenACWY uptake amongst students in this study and in other sources is above the national coverage for all adolescents (35.3%), indicating that this vaccination programme may be increasing health inequalities. Older students are less likely to become vaccinated due to differing vaccination policy in this age-group. In future, strategies that focus on specific student cohorts and that highlight vaccine effectiveness and the risk of meningitis should be considered. National evaluation of this vaccination programme is recommended to clarify its impact on health inequalities.

In-season and out-of-season variation of rotavirus genotype distribution and age of infection across 12 European countries before the introduction of routine vaccination, 2007/08 to 2012/13

The EuroRotaNet surveillance network has conducted rotavirus genotype surveillance since 2007 in 16 European countries. Using epidemiological and microbiological data from 39,786 genotyped rotavirus-positive specimens collected between September 2007 and August 2013, we assessed genotype distribution and age distribution of rotavirus gastroenteritis (RVGE) cases in and out of peak season in 12 countries which were yet to implement routine rotavirus vaccination. In multinomial multivariate logistic regression, adjusting for year, country and age, the odds of infection caused by genotype-constellation 2 DS-1-like stains (adjusted multinomial odds ratio (aM-OR) = 1.25; 95% confidence interval (CI): 1.13-1.37; p < 0.001), mixed or untypable genotypes (aM-OR = 1.55; 95% CI: 1.40-1.72; p < 0.001) and less common genotypes (aM-OR = 2.11; 95% CI:1.78-2.51; p < 0.001) increased out of season relative to G1P[8]. Age varied significantly between seasons; the proportion of RVGE cases younger than 12 months in the United Kingdom increased from 34% in season to 39% out of season (aM-OR = 1.66; 95% CI: 1.20-2.30), and the proportion five years and older increased from 9% in season to 17% out of season (aM-OR = 2.53; 95% CI: 1.67-3.82). This study provides further understanding of the rotavirus ecology before vaccine introduction, which will help interpret epidemiological changes in countries introducing or expanding rotavirus vaccination programmes.

Ecological assessment of the direct and indirect effects of routine rotavirus vaccination in Merseyside, UK using data from multiple health systems: a study protocol

Introduction Rotavirus is the most common cause of severe gastroenteritis in infants and young children worldwide. Currently 67 countries include rotavirus vaccine in childhood immunisation programmes, but uptake in Western Europe has been slow. In July 2013, rotavirus vaccine was introduced into the UKs routine childhood immunisation programme. Prior to vaccine introduction in the UK, rotavirus was estimated to result in 750 000 diarrhoea episodes and 80 000 general practice (GP) consultations each year, together with 45% and 20% of hospital admissions and emergency department attendances for acute gastroenteritis, in children under 5 years of age. This paper describes a protocol for an ecological study that will assess rotavirus vaccine impact in the UK, to inform rotavirus immunisation policy in the UK and in other Western European countries. Methods and analysis In Merseyside, UK, we will conduct an ecological study using a ‘before and after’ approach to examine changes in gastroenteritis and rotavirus incidence following the introduction of rotavirus vaccination. Data will be collected on mortality, hospital admissions, nosocomial infection, emergency department attendances, GP consultations and community health consultations to capture all healthcare providers in the region. We will assess both the direct and indirect effects of the vaccine on the study population. Comparisons of outcome indicator rates will be made in relation to vaccine uptake and socioeconomic status. Ethics and dissemination The study has been approved by NHS Research Ethics Committee, South Central-Berkshire REC Reference: 14/SC/1140. Study outputs will be disseminated through scientific conferences and peer-reviewed publications. The study will demonstrate the impact of rotavirus vaccination on the burden of disease from a complete health system perspective. It will identify key areas that require improved data collection tools to maximise the usefulness of this surveillance approach and will provide a template for vaccine evaluations using ecological methods in the UK.

Mitigating bias in observational vaccine effectiveness studies using simulated comparator populations: Application to rotavirus vaccination in the UK

BACKGROUND Measuring vaccine effectiveness (VE) relies on the use of observational study designs. However, achieving robust estimates of direct and indirect VE is frequently compromised by bias, particularly when using syndromic diagnoses of low-specificity. METHODS In order to mitigate confounding between the measured outcome and vaccine uptake, we developed a method to balance comparator populations using individual-level propensity scoring derived from the vaccine-exposed population, and applied it to the unexposed comparator population. Indirect VE was estimated by comparing the unvaccinated vaccine-exposed group with a propensity score-simulated unvaccinated, unexposed group. Direct VE was derived by removing indirect VE from the overall VE. We applied this method to an evaluation of the effectiveness of infant rotavirus vaccination in the UK. Using a general practice cohort of 45,259 live births between May 2010 and December 2015, we calculated indirect and direct VE against consultations for acute gastroenteritis using conventional and vaccination-propensity adjustment comparator populations. RESULTS The overall VE during the rotavirus-season (January-May) calculated using mixed-effects Cox regression was 30% [95% confidence intervals (95% CI: 25,35%)]. Use of conventional comparator populations resulted in implausible VE estimates -14% (95% CI: -41,7%) for direct and 29% (95% CI: 14,42%) for indirect effects. Applying our alternative method, direct VE was 26% (95% CI: 1,45%) and indirect VE was 8% (95% CI: -19,29%). CONCLUSIONS Estimating VE using propensity score simulated comparator populations, particularly for studies using routine health data with syndromic, low-specificity endpoints will aid accurate measurement of the broader public health impact of a vaccine programme.

Meningococcal vaccination in primary care amongst adolescents in North West England: an ecological study investigating associations with general practice characteristics

BACKGROUND In 2015 the meningococcal ACWY (MenACWY) vaccination was introduced amongst adolescents in England following increased incidence and mortality associated with meningococcal group W. METHODS MenACWY vaccination uptake data for 17-18 years old and students delivered in primary care were obtained for 20 National Health Service clinical commissioning groups (CCGs) via the ImmForm vaccination system. Data on general practice characteristics, encompassing demographics and patient satisfaction variables, were extracted from the National General Practice Profiles resource. Univariable analysis of the associations between practice characteristics and vaccination was performed, followed by multivariable negative binomial regression. RESULTS Data were utilized from 587 general practices, accounting for ~8% of all general practices in England. MenACWY vaccination uptake varied from 20.8% to 46.8% across the CCGs evaluated. Upon multivariable regression, vaccination uptake increased with increasing percentage of patients from ethnic minorities, increasing percentage of patients aged 15-24 years, increasing percentage of patients that would recommend their practice and total Quality and Outcomes Framework achievement for the practice. Conversely, vaccination uptake decreased with increasing deprivation. CONCLUSIONS This study has identified several factors independently associated with MenACWY vaccination in primary care. These findings will enable a targeted approach to improve general practice-level vaccination uptake.

Measles outbreaks in the UK, is it when and where, rather than if? A database cohort study of childhood population susceptibility in Liverpool, UK

Objectives There was a large outbreak of measles in Liverpool, UK, in 2012–2013, despite measles, mumps and rubella (MMR) immunisation uptake rates that were higher than the national average. We estimated measles susceptibility of a cohort of children born in Liverpool between 1995 and 2012 to understand whether there was a change in susceptibility before and after the outbreak and to inform vaccination strategy. Design Retrospective cohort study. Setting The city of Liverpool, North West UK. Participants All children born in Liverpool (72 101) between 1995 and 2012 inclusive who were identified using the Child Health Information System (CHIS) and were still resident within Liverpool in 2014. Primary and secondary outcome measures We estimated cohort age-disaggregated and neighbourhood-disaggregated measles susceptibility according to WHO thresholds before and after the outbreak for children aged 1–17 years. Results Susceptibility to measles was above WHO elimination thresholds before and after the measles outbreak in the 10+ age group. The proportion of children susceptible before and after outbreak, respectively: age 1–4 years 15.0% before and 14.9% after; age 5–9 years 9.9% before and 7.7% after; age 10+ years 8.6% before and 8.5% after. Despite an intensive MMR immunisation catch-up campaign after the 2012–2013 measles outbreak, the overall proportion of children with no MMR remains high at 6.1% (4390/72 351). Across all age groups and before and after the outbreak, measles susceptibility was clustered by neighbourhood, with deprived areas having the greatest proportion of susceptible children. Conclusions The risk of sustained measles outbreaks remains, especially as large pools of susceptible older children will start leaving secondary education and continue to aggregate in higher education, employment and other community settings and institutions resulting in the potential for a propagated measles outbreak.